Overall Summary/Abstract This Phase II COBRE application entitled ?Stem Cells and Aging? focuses on neural and hematopoietic stem cells, their microenvironments and the impact of aging, fibrosis, and senescence on their regulation and evolution to diseases of the central nervous system and bone marrow. The COBRE continues to be led by Dr. Peter Quesenberry, but now adds Dr. John Sedivy as Associate Director Both have a long history of funded research in areas relevant to the projects in this proposal. The mentors are all outstanding and experienced investigators with significant mentoring experience and specific expertise for their mentees. Two of our previous project leaders are now mentors. The EAC consists of 4 excellent scientists who were on the last EAC and one new member focused on aging and chromatin biology. There are 4 related projects and 2 Cores. We will build on the success of our Phase I COBRE in which we saw 5 of our 6 investigators progress in their careers and 2 individuals obtained R01 funding (3 R01s), one significant DOD funding, one Leukemia /Lymphoma Society support and one other K08 support. Total extramural support obtained by our fundees (not counting COBRE dollars) for all years was $11,283,095 and total publications were 134. We plan to employ enhanced metrics to support talented investigators and sculpt their projects so that they are competitive for garnering independent NIH support. The individual projects are 1.) Patrycja Dubielecka PhD on the role of Abelson interactive protein-1 and its effect on the microenvironment in the development of myeloid neoplasia with aging, 2.) Olin Liang PhD. on the role of aged microenvironment in normal hematopoiesis, defining the critical niche cells and the role of SHIP inhibition in vivo in reconstitution of aged and preleukemic microenvironment, 3.) Jill Kreiling PhD on the study of cellular senescence and role of retrotransposable elements, and 4.) Ashley Webb PhD to determine whether changes in the FOXO3 network underlies decline of neural stem cell function with aging. The success of our PHASE I COBRE derives from our attention to mentoring junior investigators but we will enhance this with new groups focused on Academic Advancement and Promotion and on Collaborative Grants. We will maintain our approach where we insist that our junior investigators participate in weekly meetings where we rotate from investigator to investigator in terms of keeping track of progress of their individual projects. All investigators have benefited from a close relationship with their mentors, and these will continue. Our goal here is the sequential development of successful R01 grant applications. We also realize that the growth of our investigators ultimately depends upon their ability to successfully complete academic milestones necessary for promotion, retention and eventual tenure. All of our Phase II project PIs are Assistant Professors, thus their promotion to Associate Professor will require meeting Brown milestones and as part of our Brown mentoring activities we will ensure that these milestones are met. Our long-term goal will be the development of an Institute focused on stem cells and aging.